Interview with Man Who Got Cured of HIVNelson Vergel
This link has a video of an interview with Tim Brown, the man who got cured of HIV (who I refer to as the “Berlin Patient” in my article below).
Some HIV-infected patients who have an undetectable viral load while taking HIV medications continue to have low CD4+ cell counts. Lalezari et al decided to perform their proof-of-concept study on six of these patients: Each was on HIV antiretrovirals, had an undetectable HIV viral load, had a CD4+ cell count between 200 and 500, and had been HIV infected for more than 20 years. The patients were enrolled in one of two cohorts: in one, 10 billion total cells were modified; in the other, 20 billion. The process involved autologous (i.e., derived from the patient) R5-disrupted T cells that were expanded and modified with ZFNs outside the patients’ bodies and then infused into the patients. The patients were followed weekly for one month and then monthly for 11 months post-infusion; blood and rectal mucosa samples were taken.
This novel study construction is the result of a history of groundbreaking findings. CCR5 has long been of interest to HIV researchers because many people who are resistant to HIV infection have a mutation in their CCR5 gene: the delta32 mutation. A minority of people of northern European descent (1% to 2.5%) have this mutation in the CCR5 receptor. After studying these patients, the oral CCR5 inhibitor drug maraviroc (MVC, Selzentry, Celsentri) was developed and ultimately approved in the U.S. in 2007. Fears that blocking the CCR5 receptor would lead to more rapid HIV disease progression or the emergence of other health problems have slowly dissipated since the drug was first given to humans in studies. (That said, there are some known adverse effects of CCR5 receptor blocking, including increased susceptibility to West Nile virus.)
As maraviroc was being developed, companies such as Sangamo BioSciences, Inc., were already trying to block the CCR5 receptor in a more permanent way: by using zinc finger nucleases, which act like scissors that cut the gene that codes for that receptor. But in the past, studies trying to modify CD4 cells in this manner have shown limited persistence of these cells after infusion in patients.
At the same time, some clinicians around the world were also trying to think outside the box on how to block HIV entry into CD4 cells. One such progressive thinker was Gero Hütter, M.D., from the Charité-Universitätsmedizin in Berlin. He had an HIV-infected patient with leukemia; he decided to try to treat both the patient’s leukemia and HIV via a stem cell transplant using a donor with the delta32 mutation.
Hütter (and his patient) was lucky to find such a donor. The transplant — which treats leukemia by essentially rebooting the body’s immune system and creating new white blood cells — also had the benefit of wiping out the HIV infection in the patient. The results of this extraordinary case were presented at CROI 2008 without receiving much excitement from the medical community.
It wasn’t until almost two years later — when it was found that the “Berlin patient” was still free of HIV not only in the blood, but in other compartments as well — that excitement grew. Now, four years later, the patient remains HIV-free, which suggests he is cured of the disease. This has given companies such as Sangamo even more motivation to pursue a potential functional cure via disruption of the CCR5 receptor.
The data presented by Lalezari about Sangamo’s ZFN approach showed several things:
- The infusion was safe and well tolerated.
- CD4+ cell count increases were seen in five of the six patients. The patient who did not respond had pre-existing antibodies to the adenovirus vector used to deliver the ZFN into the CD4 cell, so his body destroyed the vector, rendering the ZFN inactive. About 50% of the human population has those same antibodies, so a different vector may be used in future studies.
- The percentage of CCR5 disruption in the peripheral blood of the five responders was 6%, 3%, 1%, 2%, and 2% (respectively) at day 14 and persisted for the duration of the follow-up. CD4+ cell counts increased in all patients at day 14 (from an average of 35 to 1038 cells/mm3) and were sustained at all time points (with mean increases of 208, 86, 233, 911, 210 cells/mm3, respectively). CCR5-disrupted cells were detected in the rectal mucosa of all patients at all assessed time points, with levels of CCR5 disruption approximating that of peripheral blood when normalized for CD4 cells within each compartment.
- Three of the five responders had normalization of the CD4/CD8 ratio, which is a hallmark of the health of the immune system.
- There was a good uptake (grafting) of the modified CD4 cells into the blood of the five responders. In fact, by day 14 these patients had three times the quantity of cells that had been infused, showing that there was a growth of modified cells in their bodies. By day 90, the levels of persistent engraftment had become 6- to 40-fold greater than previously reported. After three months, 6% to 7% of the CD4 cells in the circulating blood had evidence of gene modification, which is over 10-fold higher than achieved by any previous T-cell modification therapy in HIV.
- Homing of these cells to the gut mucosa was observed in all patients tested, with CCR5 disruption levels similar to that of peripheral blood, suggesting these cells traffic normally. This is important since gut mucosa is the interface between the immune system and HIV.
- As I noted above, there were two cohorts in dosing: 10 and 20 billion cells. There seemed not to be a response difference between those two cell doses. Cells grafted and expanded during the first two weeks.
This exciting study opens the door to new possibilities, but many questions remain unanswered:
- What will happen long-term with the newly engrafted CD4 cells? Will they provide a survival or comorbidity benefit in these patients? (Note: Patients in this study will be followed for life.)
- Will this approach help control HIV replication in patients who stop antiretrovirals after long-term HIV suppression? How can we ethically ask patients to enroll in studies that require a structured treatment interruption? Will institutional review boards be willing to approve these kinds of studies in the future?
- Do people do better with more than one infusion? What is the best number of cells to ensure optimum immunological response?
- Will this approach help control HIV replication in treatment-naive patients who have a detectable viral load and who are not taking HIV antiretrovirals? Will these cells still have a survival advantage when challenged with untreated HIV? (Note: Lalezari is currently enrolling a 14-patient study in San Francisco that will attempt to answer these questions.)
- Will these gene-modified cells have a survival and activity advantage against HIV across the board? Will HIV viral load be controlled well enough for people to stop using antiretrovirals — or, as stated in the question above, allow them to avoid antiretrovirals entirely?
- What will the cost of this procedure be?
- What happens to those with pre-exposure to the adenovirus vector who cannot respond to this type of zinc finger nuclease delivery method?
We should be careful not to overreach with these data. Many people are throwing the “cure” word around when talking about this study, but this is just a very preliminary effort to start answering important questions toward that goal.
At a CROI 2011 press conference, Lalezari and other researchers involved in zinc finger nuclease and HIV gene therapy research discussed their findings and the broader implications of those findings. Click here to read that transcript.